In our proposed study, SBHW-PREDICT (The role of PRoteomics, gEnetics, and Directed Imaging using CT), we will assess whether identification of at-risk individuals, using imaging markers, a biomarker profile or a combination of the two, improves reclassification and discrimination over traditional risk factors, particularly in those wth either a family history of coronary heart disease (CHD) or higher genetic predisposition for CHD. We have used data from 1312 participants of the first NIH-funded study of predictive value of CAC, the South Bay Heart Watch (SBHW) study, to calculate plaque density. In preliminary analyses, we have found that higher plaque density is related to lower incidence of CVD events in this cohort. In the proposed study, we will use serum and cell samples collected at baseline, 20 years ago, from the SBHW and retrospectively assess outcomes using administrative data from Medicare and the National Death Index to address the following aims and objectives: 1) Using Medicare Claims and National Death Index data assess prognostic value of baseline CAC, as well as coronary calcium density for long-term (20 year) CHD event rate; 2) Using serum and cell samples collected at baseline, assess whether a multi-biomarker approach using circulating markers from different biological pathways would have additional reclassification value over traditional risk factors; 3) Determine whether compared to family history a CHD genetic risk score is more predictive of events; and 4) Determine whether a genetic score modifies the prognostic value of an imaging marker (CAC) or a multiple biomarker score or a combination of the two in those at higher predisposition (based on either family history or genetic score) for CHD versus those at low genetic risk. The experience of our multidisciplinary research team, unique 20 year follow-up period after baseline CAC, linkage to Medicare claims data and Death Index data, genetic and biomarker profiles using frozen serum and cell samples, and follow-up of the original cohort survivors are major strengths of this proposal. Results of thi project will assess the utility of a complementary genetic marker, multi-biomarker, and imaging approach to risk assessment.